Pyrazole derivatives and their use as cannabinoid receptor mediators

ABSTRACT

A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: 
                         
wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;
         Q is H, hydroxyl, or optionally-substituted alkoxy;   R 1 , R 2 , and R 3  are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R 2  and R 3  together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring;   Z is B, N, —CH—, or P;   D is —S(O) 2 — or —C(O)—; and   n is 0 to 5.

CROSS REFERENCE TO RELATED APPLICATIONS

This is the U.S. National Stage of International Application No.PCT/US2015/029946, filed May 8, 2015, which was published in Englishunder PCT Article 21(2), which in turn claims the benefit of U.S.Provisional Application No. 61/991,333, filed May 9, 2014, whichapplications are incorporated herein by reference in their entireties.

BACKGROUND

Endocannabinoids are lipid signaling molecules that act on the samecannabinoid receptors—CB₁ and CB₂—that recognize and mediate the effectsof marijuana. Activation of CB₁ receptors increases appetite, increasesthe biosynthesis and storage of lipids, inhibits the actions of insulinand leptin, and promotes inflammation and fibrosis, which has led to thedevelopment of CB₁ receptor blocking drugs for the treatment of obesityand its metabolic complications, referred to as the metabolic syndrome.The prototype compound rimonabant proved effective in the treatment ofthe metabolic syndrome, but caused neuropsychiatric side effects, whichresulted in its withdrawal from the market and halted furthertherapeutic development of this class of compounds.

SUMMARY

In one embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy;

R¹, R², and R³ are each independently selected from H,optionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,aminocarbonyl, optionally-substituted sulfonyl, optionally-substitutedaryl, optionally-substituted heteroaryl, optionally-substitutedcarboxyl, acyl, optionally-substituted alkenyl, optionally-substitutedalkynyl, optionally-substituted phosphonyl, optionally-substitutedphosphinyl, aralkyl, optionally-substituted thiol, or R² and R³ togetherwith Z form an optionally-substituted cycloalkyl ring or anoptionally-substituted heterocycloalkyl ring;

Z is B, N, —CH—, or P;

D is —S(O)₂— or —C(O)—; and

n is 0 to 5.

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy; and

U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl,optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy,optionally-substituted alkoxy, amino, aminocarbonyl,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;and R^(b) is a substituted sulfonyl or a substituted carbonyl.

Disclosed herein in a further embodiment is a compound, or apharmaceutically acceptable salt or ester thereof, comprising (i) a CB₁receptor mediating scaffold and (ii) a second therapeutic scaffold.

Disclosed herein in a further embodiment is a pharmaceutical compositioncomprising a compound disclosed herein, and at least onepharmaceutically acceptable additive.

Also disclosed herein is a composition comprising a unit dosage form ofa therapeutic amount of a compound disclosed herein, and at least onepharmaceutically acceptable additive.

Disclosed herein in a further embodiment is a method for treatingobesity, diabetes, non-alcoholic and alcoholic fatty liver disease, or aco-morbidity of obesity such as arteriosclerotic heart disease or gout,in a subject comprising administering to the subject in need thereof atherapeutically effective amount of a compound disclosed herein.

Disclosed herein in a further embodiment is a method for treatingfibrosis or liver cancer in a subject, comprising administering to thesubject in need thereof a therapeutically effective amount of a compounddisclosed herein.

Disclosed herein in a further embodiment is a method of preventing orreversing the deposition of adipose tissue in a subject, comprisingadministering to the subject in need thereof an effective amount of acompound disclosed herein.

The foregoing will become more apparent from the following detaileddescription of several embodiments, which proceeds with reference to theaccompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts one embodiment of a general synthesis method of makingthe compounds disclosed herein.

FIG. 2 depicts a further embodiment of a general synthesis method ofmaking the compounds disclosed herein.

DETAILED DESCRIPTION

Terminology

The following explanations of terms and methods are provided to betterdescribe the present compounds, compositions and methods, and to guidethose of ordinary skill in the art in the practice of the presentdisclosure. It is also to be understood that the terminology used in thedisclosure is for the purpose of describing particular embodiments andexamples only and is not intended to be limiting.

“Acyl” refers to a group having the structure —C(O)R, where R may be,for example, optionally substituted alkyl, optionally substituted aryl,or optionally substituted heteroaryl.

“Lower acyl” groups are those that contain one to six carbon atoms. Forexample, an acyl group may be (C₁-C₆)alkanoyl which can be, for exampleacetyl, propanoyl or butanoyl.

“Acyloxy” refers to a group having the structure —OC(O)R, where R maybe, for example, optionally substituted alkyl, optionally substitutedaryl, or optionally substituted heteroaryl. “Lower acyloxy” groupscontain one to six carbon atoms. For example, an acyloxy can be a(C₂-C₆)alkanoyloxy which can be, for example, acetoxy, propanoyloxy,butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy.

“Administration” as used herein is inclusive of administration byanother person to the subject or self-administration by the subject.

The term “aliphatic” is defined as including alkyl, alkenyl, alkynyl,halogenated alkyl and cycloalkyl groups. A “lower aliphatic” group is abranched or unbranched aliphatic group having from 1 to 10 carbon atoms.

“Alkanediyl,” “cycloalkanediyl,” “aryldiyl,” “alkanearyldiyl” refers toa divalent radical derived from aliphatic, cycloaliphatic, aryl, andalkanearyl hydrocarbons.

“Alkenyl” refers to a cyclic, branched or straight chain groupcontaining only carbon and hydrogen, and contains one or more doublebonds that may or may not be conjugated. Alkenyl groups may beunsubstituted or substituted. “Lower alkenyl” groups contain one to sixcarbon atoms. (C₂-C₆)alkenyl can be, for example, vinyl, allyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,4-hexenyl, or 5-hexenyl.

The term “alkoxy” refers to a straight, branched or cyclic hydrocarbonconfiguration and combinations thereof, including from 1 to 20 carbonatoms, preferably from 1 to 8 carbon atoms (referred to as a “loweralkoxy”), more preferably from 1 to 4 carbon atoms, that include anoxygen atom at the point of attachment. An example of an “alkoxy group”is represented by the formula —OR, where R can be an alkyl group,optionally substituted with an alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group.Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy,pentoxy, 3-pentoxy, or hexyloxy, and the like.

“Alkoxycarbonyl” refers to an alkoxy substituted carbonyl radical,—C(O)OR, wherein R represents an optionally substituted alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.(C₁-C₆)alkoxycarbonyl can be, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, or hexyloxycarbonyl.

The term “alkyl” refers to a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl,octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A“lower alkyl” group is a saturated branched or unbranched hydrocarbonhaving from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4carbon atoms. Alkyl groups may be “substituted alkyls” wherein one ormore hydrogen atoms are substituted with a substituent such as halogen,cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. Forexample, a lower alkyl or (C₁-C₆)alkyl can be methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; halo(C₁-C₆)alkyl can be iodomethyl, bromomethyl,chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl,2-fluoroethyl, 2,2,2-tiifluoroethyl, or pentafluoroethyl; orhydroxy(C₁-C₆)alkyl can be hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl,1-hydroxyhexyl, or 6-hydroxyhexyl.

“Alkynyl” refers to a cyclic, branched or straight chain groupcontaining only carbon and hydrogen, and unless otherwise mentionedtypically contains one to twelve carbon atoms, and contains one or moretriple bonds. Alkynyl groups may be unsubstituted or substituted. “Loweralkynyl” groups are those that contain two to six carbon atoms.(C₂-C₆)alkynyl, for example, can be ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl;

The term “amine” or “amino” refers to a group of the formula —NRR′,where R and R′ can be, independently, hydrogen or an alkyl, alkenyl,alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, orheterocycloalkyl group. For example, an “alkylamino” or “alkylatedamino” refers to —NRR′, wherein at least one of R or R′ is an alkyl.

The term “aminoalkyl” refers to alkyl groups as defined above where atleast one hydrogen atom is replaced with an amino group (e.g, —CH₂—NH₂).

“Aminocarbonyl” alone or in combination, means an amino substitutedcarbonyl (carbamoyl) radical, wherein the amino radical may optionallybe mono- or di-substituted, such as with alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyland the like. An aminocarbonyl group may be —N(R)—C(O)-R (wherein R is asubstituted group or H). A suitable aminocarbonyl group is acetamido.

The term “amide” or “amido” is represented by the formula —C(O)NRR′,where R and R′ independently can be a hydrogen, alkyl, alkenyl, alkynyl,aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.

An “analog” is a molecule that differs in chemical structure from aparent compound, for example a homolog (differing by an increment in thechemical structure or mass, such as a difference in the length of analkyl chain or the inclusion of one of more isotopes), a molecularfragment, a structure that differs by one or more functional groups, ora change in ionization. An analog is not necessarily synthesized fromthe parent compound. A derivative is a molecule derived from the basestructure.

An “animal” refers to living multi-cellular vertebrate organisms, acategory that includes, for example, mammals and birds. The term mammalincludes both human and non-human mammals. Similarly, the term “subject”includes both human and non-human subjects, including birds andnon-human mammals, such as non-human primates, companion animals (suchas dogs and cats), livestock (such as pigs, sheep, cows), as well asnon-domesticated animals, such as the big cats. The term subject appliesregardless of the stage in the organism's life-cycle. Thus, the termsubject applies to an organism in utero or in ovo, depending on theorganism (that is, whether the organism is a mammal or a bird, such as adomesticated or wild fowl).

The term “aralkyl” refers to an alkyl group wherein an aryl group issubstituted for a hydrogen of the alkyl group. An example of an aralkylgroup is a benzyl group.

“Aryl” refers to a monovalent unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl), which can optionally be unsubstituted orsubstituted. A “heteroaryl group,” is defined as an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorous. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl, and the like. The aryl or heteroaryl groupcan be substituted with one or more groups including, but not limitedto, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone,aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroarylgroup can be unsubstituted.

“Aryloxy” or “heteroaryloxy” refers to a group of the formula —OAr,wherein Ar is an aryl group or a heteroaryl group, respectively.

“Carbonyl” refers to —C(O).

The term “carboxylate” or “carboxyl” refers to the group —COO⁻ or —COOH.The carboxyl group can form a carboxylic acid. “Substituted carboxyl”refers to —COOR where R is alkyl, alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, halogenated alkyl, or heterocycloalkyl group. For example, asubstituted carboxyl group could be a carboxylic acid ester or a saltthereof (e.g., a carboxylate).

The term “co-administration” or “co-administering” refers toadministration of a compound disclosed herein with at least one othertherapeutic or diagnostic agent within the same general time period, anddoes not require administration at the same exact moment in time(although co-administration is inclusive of administering at the sameexact moment in time). Thus, co-administration may be on the same day oron different days, or in the same week or in different weeks.

The term “cycloalkyl” refers to a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. The term “heterocycloalkyl group” is acycloalkyl group as defined above where at least one of the carbon atomsof the ring is substituted with a heteroatom such as, but not limitedto, nitrogen, oxygen, sulfur, or phosphorous.

The term “ester” refers to a carboxyl group-containing moiety having thehydrogen replaced with, for example, a C₁₋₆alkyl group(“carboxylC₁₋₆alkyl” or “alkylester”), an aryl or aralkyl group(“arylester” or “aralkylester”) and so on. CO₂C₁₋₃alkyl groups arepreferred, such as for example, methylester (CO₂Me), ethylester (CO₂Et)and propylester (CO₂Pr) and includes reverse esters thereof (e.g.—OCOMe, —OCOEt and —OCOPr).

The terms “halogenated alkyl” or “haloalkyl group” refer to an alkylgroup with one or more hydrogen atoms present on these groupssubstituted with a halogen (F, Cl, Br, I).

The term “hydroxyl” is represented by the formula —OH.

The term “hydroxyalkyl” refers to an alkyl group that has at least onehydrogen atom substituted with a hydroxyl group. The term “alkoxyalkylgroup” is defined as an alkyl group that has at least one hydrogen atomsubstituted with an alkoxy group described above.

“Inhibiting” refers to inhibiting the full development of a disease orcondition. “Inhibiting” also refers to any quantitative or qualitativereduction in biological activity or binding, relative to a control.

“N-heterocyclic” or “N-heterocycle” refers to mono or bicyclic rings orring systems that include at least one nitrogen heteroatom. The rings orring systems generally include 1 to 9 carbon atoms in addition to theheteroatom(s) and may be saturated, unsaturated or aromatic (includingpseudoaromatic). The term “pseudoaromatic” refers to a ring system whichis not strictly aromatic, but which is stabilized by means ofdelocalization of electrons and behaves in a similar manner to aromaticrings. Aromatic includes pseudoaromatic ring systems, such as pyrrolylrings.

Examples of 5-membered monocyclic N-heterocycles include pyrrolyl,H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl,isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls),tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), anddithiazolyl. Examples of 6-membered monocyclic N-heterocycles includepyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, and triazinyl. The heterocycles may beoptionally substituted with a broad range of substituents, andpreferably with C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono ordi(C₁₋₆alkyl)amino. The N-heterocyclic group may be fused to acarbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl,and anthracenyl.

Examples of 8, 9 and 10-membered bicyclic heterocycles include 1Hthieno[2,3-c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl,indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like.These heterocycles may be optionally substituted, for example with C₁₋₆alkyl, C₁₋₆ alkoxy, alkenyl, C₂₋₆ alkynyl, halo, hydroxy, mercapto,trifluoromethyl, amino, cyano or mono or di(C₁₋₆alkyl)amino. Unlessotherwise defined optionally substituted N-heterocyclics includespyridinium salts and the N-oxide form of suitable ring nitrogens.

The term “subject” includes both human and non-human subjects, includingbirds and non-human mammals, such as non-human primates, companionanimals (such as dogs and cats), livestock (such as pigs, sheep, cows),as well as non-domesticated animals, such as the big cats. The termsubject applies regardless of the stage in the organism's life-cycle.Thus, the term subject applies to an organism in utero or in ovo,depending on the organism (that is, whether the organism is a mammal ora bird, such as a domesticated or wild fowl).

“Substituted” or “substitution” refers to replacement of a hydrogen atomof a molecule or an R-group with one or more additional R-groups. Unlessotherwise defined, the term “optionally-substituted” or “optionalsubstituent” as used herein refers to a group which may or may not befurther substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or3, more preferably 1 or 2 groups. The substituents may be selected, forexample, from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,hydroxyl, oxo, C₁₋₆alkoxy, aryloxy, C₁₋₆alkoxyaryl, halo, C₁₋₆alkylhalo(such as CF₃ and CHF₂). C₁₋₆alkoxyhalo (such as OCF₃ and OCHF₂),carboxyl, esters, cyano, nitro, amino, substituted amino, disubstitutedamino, acyl, ketones, amides, aminoacyl, substituted amides,disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates,sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl,sulfonylamides, substituted sulfonamides, disubstituted sulfonamides,aryl, arC₁₋₆alkyl, heterocyclyl and heteroaryl wherein each alkyl,alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groupscontaining them may be further optionally substituted. Optionalsubstituents in the case N-heterocycles may also include but are notlimited to C₁₋₆alkyl i.e. N—C₁₋₃alkyl, more preferably methylparticularly N-methyl.

“Sulfinyl” refers to the group —S(═O)H.

The term “substituted sulfinyl” or “sulfoxide” refers to a sulfinylgroup having the hydrogen replaced with, for example a C₁₋₆alkyl group(“C₁₋₆alkylsulfinyl” or “C₁₋₆alkylsulfoxide”), an aryl (“arylsulfinyl”),an aralkyl (“aralkyl sulfinyl”) and so on. C₁₋₃alkylsulfinyl groups arepreferred, such as for example, —SOmethyl, —SOethyl and —SOpropyl.

The term “sulfonyl” refers to the group —SO₂H.

The term “substituted sulfonyl” refers to a sulfonyl group having thehydrogen replaced with, for example a C₁₋₆alkyl group(“sulfonylC₁₋₆alkyl”), an aryl (“arylsulfonyl”), an aralkyl(“aralkylsulfonyl”), a heteroaryl, a cycloalkyl, a heterocycloalkyl, andso on. SulfonylC₁₋₃alkyl groups are preferred, such as for example,—SO₂Me, —SO₂Et and —SO₂Pr.

The term “sulfonylamido” or “sulfonamide” refers to the group —SO₂NH₂.

A “therapeutically effective amount” refers to a quantity of a specifiedagent sufficient to achieve a desired effect in a subject being treatedwith that agent. Ideally, a therapeutically effective amount of an agentis an amount sufficient to inhibit or treat the disease or conditionwithout causing a substantial cytotoxic effect in the subject. Thetherapeutically effective amount of an agent will be dependent on thesubject being treated, the severity of the affliction, and the manner ofadministration of the therapeutic composition.

“Thiol” refers to the group —SH.

The term “substituted thiol” refers to a thiol group having the hydrogenreplaced with, for example a C₁₋₆alkyl group (“—S(C₁₋₆alkyl)”), an aryl(“—S(aryl)”), or an aralkyl (“—S(alkyl)(aryl)”) and so on.(C₁-C₆)alkylthio, for example, can be methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio.

“Treatment” refers to a therapeutic intervention that ameliorates a signor symptom of a disease or pathological condition after it has begun todevelop, or administering a compound or composition to a subject whodoes not exhibit signs of a disease or exhibits only early signs for thepurpose of decreasing the risk of developing a pathology or condition,or diminishing the severity of a pathology or condition. As used herein,the term “ameliorating,” with reference to a disease or pathologicalcondition, refers to any observable beneficial effect of the treatment.The beneficial effect can be evidenced, for example, by a delayed onsetof clinical symptoms of the disease in a susceptible subject, areduction in severity of some or all clinical symptoms of the disease, aslower progression of the disease, an improvement in the overall healthor well-being of the subject, or by other parameters well known in theart that are specific to the particular disease. The phrase “treating adisease” refers to inhibiting the full development of a disease, forexample, in a subject who is at risk for a disease such as diabetes.“Preventing” a disease or condition refers to prophylactic administeringa composition to a subject who does not exhibit signs of a disease orexhibits only early signs for the purpose of decreasing the risk ofdeveloping a pathology or condition, or diminishing the severity of apathology or condition. In certain embodiments disclosed herein, thetreatment inhibits food intake or weight gain in a subject. In certainembodiments disclosed herein, the treatment inhibits fibrogenesis orreverses insulin resistance in a subject.

“Pharmaceutical compositions” are compositions that include an amount(for example, a unit dosage) of one or more of the disclosed compoundstogether with one or more non-toxic pharmaceutically acceptableadditives, including carriers, diluents, and/or adjuvants, andoptionally other biologically active ingredients. Such pharmaceuticalcompositions can be prepared by standard pharmaceutical formulationtechniques such as those disclosed in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. (19th Edition).

The terms “pharmaceutically acceptable salt or ester” refers to salts oresters prepared by conventional means that include salts, e.g., ofinorganic and organic acids, including but not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonicacid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid,tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid,maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelicacid and the like. “Pharmaceutically acceptable salts” of the presentlydisclosed compounds also include those formed from cations such assodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and frombases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, andtetramethylammonium hydroxide. These salts may be prepared by standardprocedures, for example by reacting the free acid with a suitableorganic or inorganic base. Any chemical compound recited in thisspecification may alternatively be administered as a pharmaceuticallyacceptable salt thereof. “Pharmaceutically acceptable salts” are alsoinclusive of the free acid, base, and zwitterionic forms. Descriptionsof suitable pharmaceutically acceptable salts can be found in Handbookof Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH(2002). When compounds disclosed herein include an acidic function suchas a carboxy group, then suitable pharmaceutically acceptable cationpairs for the carboxy group are well known to those skilled in the artand include alkaline, alkaline earth, ammonium, quaternary ammoniumcations and the like. Such salts are known to those of skill in the art.For additional examples of “pharmacologically acceptable salts,” seeBerge et al., J. Pharm. Sci. 66:1 (1977).

“Pharmaceutically acceptable esters” includes those derived fromcompounds described herein that are modified to include a carboxylgroup. An in vivo hydrolysable ester is an ester, which is hydrolysed inthe human or animal body to produce the parent acid or alcohol.Representative esters thus include carboxylic acid esters in which thenon-carbonyl moiety of the carboxylic acid portion of the ester groupingis selected from straight or branched chain alkyl (for example, methyl,n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example,methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example,phenoxymethyl), aryl (for example, phenyl, optionally substituted by,for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy) or amino);sulphonate esters, such as alkyl- or aralkylsulphonyl (for example,methanesulphonyl); or amino acid esters (for example, L-valyl orL-isoleucyl). A “pharmaceutically acceptable ester” also includesinorganic esters such as mono-, di-, or tri-phosphate esters. In suchesters, unless otherwise specified, any alkyl moiety presentadvantageously contains from 1 to 18 carbon atoms, particularly from 1to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Anycycloalkyl moiety present in such esters advantageously contains from 3to 6 carbon atoms. Any aryl moiety present in such esters advantageouslycomprises a phenyl group, optionally substituted as shown in thedefinition of carbocycylyl above. Pharmaceutically acceptable estersthus include C₁-C₂₂ fatty acid esters, such as acetyl, t-butyl or longchain straight or branched unsaturated or omega-6 monounsaturated fattyacids such as palmoyl, stearoyl and the like. Alternative aryl orheteroaryl esters include benzoyl, pyridylmethyloyl and the like any ofwhich may be substituted, as defined in carbocyclyl above. Additionalpharmaceutically acceptable esters include aliphatic L-amino acid esterssuch as leucyl, isoleucyl and especially valyl.

For therapeutic use, salts of the compounds are those wherein thecounter-ion is pharmaceutically acceptable. However, salts of acids andbases which are non-pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds are ableto form. The pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds containing an acidic proton may also be converted intotheir non-toxic metal or amine addition salt forms by treatment withappropriate organic and inorganic bases. Appropriate base salt formscomprise, for example, the ammonium salts, the alkali and earth alkalinemetal salts, e.g. the lithium, sodium, potassium, magnesium, calciumsalts and the like, salts with organic bases, e.g. the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like.

The term “addition salt” as used hereinabove also comprises the solvateswhich the compounds described herein are able to form. Such solvates arefor example hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds are able to form by reaction betweena basic nitrogen of a compound and an appropriate quaternizing agent,such as, for example, an optionally substituted alkylhalide, arylhalideor arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactantswith good leaving groups may also be used, such as alkyltrifluoromethanesulfonates, alkyl methanesulfonates, and alkylp-toluenesulfonates. A quaternary amine has a positively chargednitrogen. Pharmaceutically acceptable counterions include chloro, bromo,iodo, trifluoroacetate and acetate. The counterion of choice can beintroduced using ion exchange resins.

Prodrugs of the disclosed compounds also are contemplated herein. Aprodrug is an active or inactive compound that is modified chemicallythrough in vivo physiological action, such as hydrolysis, metabolism andthe like, into an active compound following administration of theprodrug to a subject. The term “prodrug” as used throughout this textmeans the pharmacologically acceptable derivatives such as esters,amides and phosphates, such that the resulting in vivo biotransformationproduct of the derivative is the active drug as defined in the compoundsdescribed herein. Prodrugs preferably have excellent aqueous solubility,increased bioavailability and are readily metabolized into the activeinhibitors in vivo. Prodrugs of a compounds described herein may beprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either by routine manipulationor in vivo, to the parent compound. The suitability and techniquesinvolved in making and using prodrugs are well known by those skilled inthe art. F or a general discussion of prodrugs involving esters seeSvensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard,Design of Prodrugs, Elsevier (1985).

The term “prodrug” also is intended to include any covalently bondedcarriers that release an active parent drug of the present invention invivo when the prodrug is administered to a subject. Since prodrugs oftenhave enhanced properties relative to the active agent pharmaceutical,such as, solubility and bioavailability, the compounds disclosed hereincan be delivered in prodrug form. Thus, also contemplated are prodrugsof the presently disclosed compounds, methods of delivering prodrugs andcompositions containing such prodrugs. Prodrugs of the disclosedcompounds typically are prepared by modifying one or more functionalgroups present in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to yield the parentcompound. Prodrugs include compounds having a phosphonate and/or aminogroup functionalized with any group that is cleaved in vivo to yield thecorresponding amino and/or phosphonate group, respectively. Examples ofprodrugs include, without limitation, compounds having an acylated aminogroup and/or a phosphonate ester or phosphonate amide group. Inparticular examples, a prodrug is a lower alkyl phosphonate ester, suchas an isopropyl phosphonate ester.

Protected derivatives of the disclosed compounds also are contemplated.A variety of suitable protecting groups for use with the disclosedcompounds are disclosed in Greene and Wuts, Protective Groups in OrganicSynthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.

In general, protecting groups are removed under conditions that will notaffect the remaining portion of the molecule. These methods are wellknown in the art and include acid hydrolysis, hydrogenolysis and thelike. One preferred method involves the removal of an ester, such ascleavage of a phosphonate ester using Lewis acidic conditions, such asin TMS-Br mediated ester cleavage to yield the free phosphonate. Asecond preferred method involves removal of a protecting group, such asremoval of a benzyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxy-based group, including t-butoxycarbonyl protecting groups can be removed utilizing an inorganic ororganic acid, such as HCl or trifluoroacetic acid, in a suitable solventsystem, such as water, dioxane and/or methylene chloride. Anotherexemplary protecting group, suitable for protecting amino and hydroxyfunctions amino is trityl. Other conventional protecting groups areknown and suitable protecting groups can be selected by those of skillin the art in consultation with Greene and Wuts, Protective Groups inOrganic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When anamine is deprotected, the resulting salt can readily be neutralized toyield the free amine. Similarly, when an acid moiety, such as aphosphonic acid moiety is unveiled, the compound may be isolated as theacid compound or as a salt thereof.

Compounds

Disclosed herein are novel peripherally restricted cannabinoid receptormediating compounds for the treatment of, for example, fibrosis,diabetes, obesity and liver cancer. The cannabinoid receptor may be CB₁and/or CB₂ receptors. The compounds may be essentially non-selective forCB₁ versus CB₂, or show selectivity for either the CB₁ receptor or theCB₂ receptor. In a preferred embodiment, the cannabinoid receptormediating compounds are selective of CB₁ receptors.

In certain embodiments, the cannabinoid receptor mediating compounds arecannabinoid receptor inverse agonists, particularly CB₁ inverseagonists. In certain embodiments, the cannabinoid receptor mediatingcompounds are neutral antagonists. A CB₁ inverse agonist is a drug thaton its own produces an effect opposite to that of a CB₁ agonist, and isalso able to block the effect of a CB₁ agonist. In contrast, a CB₁neutral antagonist can only do the latter (i.e. blocking the effect of aCB₁ agonist), but has no effect on its own. CB₁ inverse agonism isusually documented by the ability of a drug to decrease GTPgammaSbinding and/or to increase adenylate cyclase activity. The compounds mayshow functional bias for GTPgammaS or β-Arrestin or activity for bothGTPgammaS and β-Arrestin.

In certain embodiments, the compounds preferentially target CB₁receptors in peripheral tissue (e.g., adipose tissue, liver, muscle,lung, kidney, macrophages, pancreatic beta cells and gastrointestinaltract), while not interacting with CB₁ receptors in brain tissue.Peripherally-mediated effects are maintained, but CNS side effects areminimal or non-existent.

There is evidence that the metabolic effects of endocannabinoids aremediated, at least in part, by CB₁ receptors in peripheral tissues,whereas the neuropsychiatric side effects are mediated by CB₁ receptorin the brain. This suggests CB₁ receptor blocking drugs with reducedability to penetrate the brain would cause fewer if any neuropsychiatricside effects while retaining some or most of their metabolic benefits.As to limited metabolic efficacy of CB₁ receptor blocking drugs, thiscould be improved by the design of dual activity compounds that act onmore than one target in the cell to influence the same metabolicprocess. As an example, such secondary targets could include, but notlimited to, the enzyme inducible nitric oxide synthase (iNOS) oradenosine monophosphate kinase (AMPK), as suggested by findings thatinhibition of iNOS or activation of AMPK improves insulin resistance,and reduces fibrosis and inflammation (Shinozaki S et al., J. Biol.Chem. 2012, 286(40), 34959-34975; Young R J et al., Bioorg. Med. ChemLet. 2000, 10(6), 597-600; da Silva Morais A et al., Clin. Sci. 2010,118(6), 411-420). Certain embodiments disclosed herein are CB₁ blockingcompounds that have very low brain penetrance, and give rise tometabolites that either inhibit iNOS or activate AMPK directly.

In certain embodiments, a peripherally restricted cannabinoid CB₁receptor mediating compound may be characterized and can be identifiedfrom a ratio of maximum concentration in the brain to maximumconcentration in plasma which is less than 0.1, as measured in a mouseafter intravenous dosing. The preferred peripherally restrictedcannabinoid CB₁ receptor mediating compounds have a brain C_(max) toplasma C_(max) ratio which is less than 0.05. Especially preferredperipherally restricted cannabinoid receptor mediating compounds have abrain C_(max) to plasma C_(max) ratio which is less than 0.025.

In one embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy;

R¹, R², and R³ are each independently selected from H,optionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,aminocarbonyl, optionally-substituted sulfonyl, optionally-substitutedaryl, optionally-substituted heteroaryl, optionally-substitutedcarboxyl, acyl, optionally-substituted alkenyl, optionally-substitutedalkynyl, optionally-substituted phosphonyl, optionally-substitutedphosphinyl, aralkyl, optionally-substituted thiol, or R² and R³ togetherwith Z form an optionally-substituted cycloalkyl ring or anoptionally-substituted heterocycloalkyl ring;

Z is B, N. —CH—, or P;

D is —S(O)₂— or —C(O)—; and

n is 0 to 5.

In certain embodiments of formula I, R² and R³ together with Z do notform an optionally-substituted cycloalkyl ring or anoptionally-substituted heterocycloalkyl ring. In certain embodiments offormula I, R² and R³ are each independently optionally-substituted alkyl(particularly lower alkyl). In certain embodiments of formula I, R² andR³ are each independently alkyl (particularly lower alkyl). In certainembodiments of formula I, R² and R³ are each the same (particularlylower alkyl). In certain embodiments of formula I, Z is N and R² and R³together with Z do not form an optionally-substituted cycloalkyl ring oran optionally-substituted heterocycloalkyl ring. In certain embodimentsof formula I, Z is N and R² and R³ are each independently alkyl(particularly lower alkyl) or aralkyl. In certain embodiments of formulaI, Z is N and R² and R³ are each the same (particularly lower alkyl). Incertain embodiments of formula I, D is —S(O)₂—.

Further disclosed herein is a compound, or a pharmaceutically acceptablesalt or ester thereof, having a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle. In certainembodiments, the N-heterocycle of R²⁵ may be selected from pyrrolyl,H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl,isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls),tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls),dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

In certain embodiments of formulae I or Ia, each of X and Y isoptionally-substituted aryl.

Further disclosed herein is a compound, or a pharmaceutically acceptablesalt or ester thereof, having a structure of:

wherein each of R⁴, R¹⁰ and R¹¹ is independently selected fromoptionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, monoor di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono ordi-substituted C-aryl, mono or di-substituted C-cycloalkyl,—CH(COOR²⁰)—, —CH(CN)—. —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ isH or alkyl;

a and b are each 0 to 5; and

c is 0 to 7.

Further disclosed herein is a compound, or a pharmaceutically acceptablesalt or ester thereof, having a structure of:

Further disclosed herein is a compound, or a pharmaceutically acceptablesalt or ester thereof, having a structure of:

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy; and

U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl,optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy,optionally-substituted alkoxy, amino, aminocarbonyl,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;and R^(b) is a substituted sulfonyl or a substituted carbonyl.

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein R², and R³ are each independently selected from H,optionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, optionally-substituted phosphinyl, orR² and R³ together with Z form an optionally-substituted cycloalkylring, an optionally-substituted heterocycloalkyl ring; anoptionally-substituted aryl ring, or an optionally-substitutedheteroaryl ring;

Z is B, N, —CH—, or P; and

n is 0 to 5.

In certain embodiments of formula IIa, R² and R³ together with Z do notform an optionally-substituted cycloalkyl ring or anoptionally-substituted heterocycloalkyl ring. In certain embodiments offormula IIa, R² and R³ are each independently optionally-substitutedalkyl (particularly lower alkyl). In certain embodiments of formula IIa,R² and R³ are each independently alkyl (particularly lower alkyl). Incertain embodiments of formula IIa, R² and R³ are each the same(particularly lower alkyl). In certain embodiments of formula IIa, Z isN and R² and R³ together with Z do not form an optionally-substitutedcycloalkyl ring or an optionally-substituted heterocycloalkyl ring. Incertain embodiments of formula IIa, Z is N and R² and R³ are eachindependently alkyl (particularly lower alkyl) or aralkyl. In certainembodiments of formula IIa, Z is N and R² and R³ are each the same(particularly lower alkyl).

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein each R¹² is independently selected from optionally-substitutedalkyl, optionally-substituted heteroalkyl, hydroxy,optionally-substituted alkoxy or optionally-substituted alkylamino,optionally-substituted aryl, halogen, cyano, nitro, acyl or carbonyl;and d is 0 to 5.

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein R²⁵ is an optionally-substituted N-heterocycle. In certainembodiments, the N-heterocycle of R²⁵ may be selected from pyrrolyl,H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl,isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls),tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls),dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

In certain embodiments of formula II, IIa, IIb or IIc, each of X and Yis optionally-substituted aryl or optionally-substituted heteroaryl.

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

wherein each of R¹³, R¹⁴ and R¹⁵ is independently selected fromoptionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, monoor di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono ordi-substituted C-aryl, mono or di-substituted C-cycloalkyl,—CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ isH or alkyl;

f and g are each 0 to 5; and

g is 0 to 7.

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

In a further embodiment, there is disclosed herein a compound, or apharmaceutically acceptable salt or ester thereof, having a structureof:

In certain embodiments, the compounds disclosed herein may exist as a‘NH₂’ tautomer, or a ‘NH’ tautomer, or a combination of both. Forexample:

Thus, also disclosed herein are the ‘NH₂’ tautomers of Formula I andFormula II (wherein the substituents are as defined above) as follows:

Formula II* wherein U is

In certain embodiments of any of the above formulae, R¹ isoptionally-substituted alkyl (e.g., lower alkyl, thiol-substituted loweralkyl), aminocarbonyl (e.g., acetamido), or optionally-substitutedphenyl (e.g., halogen-substituted phenyl, particularly4-halogen-phenyl).

In certain embodiments of any of the above formulae, Q is H.

In certain embodiments of any of the above formulae, A is —CH₂—, —O—,—CH(CF₃)—, —N(alkyl)-, or mono or di-substituted C-aryl.

Particular examples of the presently disclosed compounds include one ormore asymmetric centers; thus these compounds can exist in differentstereoisomeric forms. Accordingly, compounds and compositions may beprovided as individual pure enantiomers or as stereoisomeric mixtures,including racemic mixtures. In certain embodiments the compoundsdisclosed herein are synthesized in or are purified to be insubstantially enantiopure form, such as in a 90% enantiomeric excess, a95% enantiomeric excess, a 97% enantiomeric excess or even in greaterthan a 99% enantiomeric excess, such as in enantiopure form.

For example, compounds of formula I may be in the form of astereoisomeric mixture or cis/trans isomers, rotamers or tautomers. Incertain embodiments, the compounds of formula I may be provided as anS-enantiomer, for example, as shown below:

In certain embodiments, the agents disclosed herein are hybrid compoundsthat include (i) a CB₁ receptor mediating scaffold (e.g., an inverseagonist or neutral antagonist) and (ii) a second therapeutic scaffold.In certain embodiments, the —NH—C(NH)R¹— moiety or —N═C(NH2)R¹— moietyin any of the formulae disclosed herein constitutes at least a portionof the second therapeutic scaffold. In certain embodiments, the secondtherapeutic scaffold may undergo in vivo cleavage, thereby releasing thesecond therapeutic scaffold which may retain at least a portion of itstherapeutic activity. For example, in the case of metformin as thesecond therapeutic scaffold, the resulting hybrid compound could havetherapeutic efficacy not only due to its blockade of CB₁ receptors, butalso due to the release of metformin, a widely used antidiabetic agent,during the in vivo metabolism of the compound. The in vivo cleavage mayoccur at any location in the body, but typically occurs in the liver,via the action of drug metabolizing enzymes, such as isoforms ofcytochrome P450. In certain embodiments, the cleavage occurs at the bondbetween the —NH—C(NH)R¹— moiety or the —N═C(NH₂)R¹— moiety and the Catom of the carboximidiamide portion of the compound.

Illustrative second therapeutic scaffolds include an antidiabetic agent,an anticancer agent, an antiobesity agent, and an antifibrotic agent.

The second therapeutic scaffold is either implicit as shown below or asan explicit attachment at the unsubstituted nitrogen end:

In certain embodiments, the compounds disclosed herein have improvedchemical stability resulting in a plasma half-life in the 1-16 hoursrange, more particularly 4-8 hours range.

In certain embodiments, the agents disclosed herein are hybrid compoundsthat include (i) a CB₁ receptor mediating scaffold (e.g., an inverseagonist or neutral antagonist) and (ii) a diagnostic agent or entity. Incertain embodiments, the —NH—C(NH)R¹— moiety or the —N═C(NH₂)R¹— moietyin any of the formulae disclosed herein constitutes at least a portionof the diagnostic agent or entity (for example, an antibody, biotin tag,¹⁸F, or ¹¹C-bearing group). Alternatively the diagnostic moiety for PET,SPECT imaging, autoradiography, can be obtained by replacing atoms inthe X, Y or Q portion of any of the formulae yielding high affinityligands, with radioisotopic atoms like ²H, ³H, ¹¹C, ¹³N, ¹⁵O, ¹⁸F,⁷⁵⁻⁷⁷Br, ¹²³⁻¹³¹I, or ^(99m)Tc. The diagnostic group or entity can beused in the imaging diagnosis of pathologies, like fibrosis, cancer,cardiovascular, metabolic, inflammatory and neurodegenerative diseases.The diagnostic compounds can be used as fluorescent probes, affinitylabels, in nuclear medicine, optical imaging, like PET, SPECT etc. Thesecompounds comprise a targeting CB₁ scaffold linked to at least adiagonstic signal entity. A CB₁ scaffold bearing the diagnostic entitywould be capable of targeting at least one marker of a pathologic state,for example proteins, enzymes or cell receptors that are expressed in apathologic state.

In certain embodiments, the compounds disclosed herein have low or nocytochrome P450 activity meaning that the agents may result in few, ifany, drug-to-drug interactions.

In certain embodiments, the compounds disclosed herein have a CB₁Rbinding affinity in the range of 0.1 to 20 nM, and CB₁/CB₂selectivity ofat least 20-fold, or more particularly 100-fold or greater.

FIGS. 1 and 2 depicts general synthesis methods for making the compoundsdisclosed herein. Synthesis Scheme I describes the general route toconvert commercially available suitably substituted2-phenylacetophenones to novel CB₁-selective inverse agonist compoundswith dual activity. The synthesis procedure applies to1,3,4-trisubstituted 4,5-dihydropyrazoles of formula I. For example,1-(4-chlorophenyl)-2-phenylethanone can be converted to1-(4-chlorophenyl)-2-phenylprop-2-en-1-one using 37% formaldehydecontaining piperidine and acetic acid (step a). Treatment of theacrylophenone with hydrazine hydrate in refluxing 2-propanol produces3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (step b) (J. Agric.Food Chem. 1979, 27, 406).The pyrazoline was condensed withsulfonylcarbamate of the type Compound VI obtained fromchlorosulfonylisocyanate(step c and d) to give the diarylpyrazolineacylsulfonamide Compound VII (step e). Chlorination of this product withphosphorus pentachloride in refluxing chlorobenzene gave theimidoylchloride Compound VIII (step f) as previously described (J. MedChe. 2004, 47, 627, and Che, Ber. 1966, 99, 2885, Bioorg Med. Chem.Lett, 2010, 20, 1752). The imidoyl chloride was coupled with compoundslike acetamidine hydrochloride in the presence of triethylamine in amixture of methanol and dichloromethane (step g) to yield4,5-dihydro-1H-pyrazole-1-carboximidamide compounds like Compound IX.This compound can be subjected to preparative HPLC conditions using achiral column to give R and S optically pure enantiomers. Alternatively,the racemic diarylpyrazoline acylsulfonamide can be separated on achiral column to give optically pure enantiomeric acyl sulfonamideswhich can be individually subjected to further manipulations as shown instep f and g.

Synthesis Scheme II describes the general route to convert commerciallyavailable aldehydes and hydrazines to novel CB₁-selective inverseagonist compounds with dual activity. The synthesis procedure applies to1,3,5-trisubstituted 4,5-dihydropyrazoles of formula II. The synthesiscan be adapted from references Bioorg Med. Chem. Lett, 2010, 20, 1752and/or J. Med Che. 2007, 50, 5951.Treatment of an aldehyde likebenzaldehyde with pyruvic acid as in step a followed by treatment withacetyl chloride in dry ethanol (step b) affords the u43-unsaturated ketoester Compound XI. Refluxing 4-chlorophenyl hydrazine and Compound XI ina solution of ethanol and acetic acid (step c) gave the dihydropyrazoleester Compound XII. Hydrolysis of the ester in alcoholic KOH gave thecoupling precursor acid Compound XIII (step d). The acid can be coupledunder basic conditions using a suitably substituted phenyl sulfonamides(step e) or suitably substituted amino sulfonamides (step f) to yieldacylsulfonamides of the type compound XIV and compound XV respectively.These compound each can be individually converted to the imidoylchloride (Compounds XVI and XVII) by treatment with PCl₅ in refluxingchlorobenzene or POCl₃ treatment in presence of a base (step g).Reaction with compounds like acetamidine or SMethyl thiourea in presenceof a base can yield final racemic compounds (XVIII and XIX) that can beseparated by chiral HPLC to give enantiopure final compounds.

Compositions and Methods of Use

The peripherally restricted cannabinoid receptor mediating agentsdisclosed herein are unique in that they may improve all, or at leastone, aspect(s) of the metabolic syndrome. They reduce food intake andbody weight, reverse insulin and leptin resistance, reverse hepaticsteatosis (fatty liver) and improve dyslipidemia. They may be used fortreating obesity, diabetes (e.g., type 2 diabetes), and non-alcoholicand alcoholic fatty liver disease (NAFLD/AFLD), the latter being a riskfactor for insulin resistance, cirrhosis and liver cancer, dyslipidemiasthat predispose to arteriosclerotic heart disease, diabetic nephropathy,gout, and fibrosis. The agents disclosed herein may be devoid of thepsychiatric side effects that prevent the use of globally acting CB₁antagonists.

The diabetes disorder may be Type 1 diabetes, Type 2 diabetes,inadequate glucose tolerance, and/or insulin resistance.

Also disclosed herein is a method for treating a co-morbidity ofobesity. The co-morbidity may be selected from diabetes, MetabolicSyndrome, dementia, and heart disease. In further embodiments, theco-morbidity is selected from hypertension; gallbladder disease;gastrointestinal disorders; menstrual irregularities; degenerativearthritis; venous statis ulcers; pulmonary hypoventilation syndrome;sleep apnea; snoring; coronary artery disease; arterial scleroticdisease; pseudotumor cerebri; accident proneness; increased risks withsurgeries; osteoarthritis; high cholesterol; and, increased incidence ofmalignancies of the liver, ovaries, cervix, uterus, breasts, prostrate,and gallbladder.

Also disclosed herein is a method of preventing or reversing thedeposition of adipose tissue in a subject. By preventing or reversingthe deposition of adipose tissue, the compounds disclosed herein areexpected to reduce the incidence or severity of obesity, therebyreducing the incidence or severity of associated co-morbidities.

Another aspect of the disclosure includes pharmaceutical compositionsprepared for administration to a subject and which include atherapeutically effective amount of one or more of the compoundsdisclosed herein. The therapeutically effective amount of a disclosedcompound will depend on the route of administration, the species ofsubject and the physical characteristics of the subject being treated.Specific factors that can be taken into account include disease severityand stage, weight, diet and concurrent medications. The relationship ofthese factors to determining a therapeutically effective amount of thedisclosed compounds is understood by those of skill in the art.

Pharmaceutical compositions for administration to a subject can includeat least one further pharmaceutically acceptable additive such ascarriers, thickeners, diluents, buffers, preservatives, surface activeagents and the like in addition to the molecule of choice.Pharmaceutical compositions can also include one or more additionalactive ingredients such as antimicrobial agents, anti-inflammatoryagents, anesthetics, and the like. The pharmaceutically acceptablecarriers useful for these formulations are conventional. Remington'sPharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton,Pa., 19th Edition (1995), describes compositions and formulationssuitable for pharmaceutical delivery of the compounds herein disclosed.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually contain injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. For solid compositions (for example, powder, pill, tablet, orcapsule forms), conventional non-toxic solid carriers can include, forexample, pharmaceutical grades of mannitol, lactose, starch, ormagnesium stearate. In addition to biologically-neutral carriers,pharmaceutical compositions to be administered can contain minor amountsof non-toxic auxiliary substances, such as wetting or emulsifyingagents, preservatives, and pH buffering agents and the like, for examplesodium acetate or sorbitan monolaurate.

Pharmaceutical compositions disclosed herein include those formed frompharmaceutically acceptable salts and/or solvates of the disclosedcompounds. Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic or organic bases and acids.Particular disclosed compounds possess at least one basic group that canform acid-base salts with acids. Examples of basic groups include, butare not limited to, amino and imino groups. Examples of inorganic acidsthat can form salts with such basic groups include, but are not limitedto, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuricacid or phosphoric acid. Basic groups also can form salts with organiccarboxylic acids, sulfonic acids, sulfo acids or phospho acids orN-substituted sulfamic acid, for example acetic acid, propionic acid,glycolic acid, succinic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconicacid, glucaric acid, glucuronic acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinicacid or isonicotinic acid, and, in addition, with amino acids, forexample with α-amino acids, and also with methanesulfonic acid,ethanesulfonic acid, 2-hydroxymethanesulfonic acid,ethane-1,2-disulfonic acid, benzenedisulfonic acid,4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 2- or3-phosphoglycerate, glucose-6-phosphate or N-cyclohexylsulfamic acid(with formation of the cyclamates) or with other acidic organiccompounds, such as ascorbic acid. In particular, suitable salts includethose derived from alkali metals such as potassium and sodium, alkalineearth metals such as calcium and magnesium, among numerous other acidswell known in the pharmaceutical art.

Certain compounds include at least one acidic group that can form anacid-base salt with an inorganic or organic base. Examples of saltsformed from inorganic bases include salts of the presently disclosedcompounds with alkali metals such as potassium and sodium, alkalineearth metals, including calcium and magnesium and the like. Similarly,salts of acidic compounds with an organic base, such as an amine (asused herein terms that refer to amines should be understood to includetheir conjugate acids unless the context clearly indicates that the freeamine is intended) are contemplated, including salts formed with basicamino acids, aliphatic amines, heterocyclic amines, aromatic amines,pyridines, guanidines and amidines. Of the aliphatic amines, the acyclicaliphatic amines, and cyclic and acyclic di- and tri- alkyl amines areparticularly suitable for use in the disclosed compounds. In addition,quaternary ammonium counterions also can be used.

Particular examples of suitable amine bases (and their correspondingammonium ions) for use in the present compounds include, withoutlimitation, pyridine, N,N-dimethylaminopyridine, diazabicyclononane,diazabicycloundecene, N-methyl-N-ethylamine, diethylamine,triethylamine, diisopropylethylamine, mono-, bis- ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine,tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine and N-methyl-D-glucamine. For additionalexamples of “pharmacologically acceptable salts,” see Berge et al., J.Pharm. Sci. 66:1 (1977).

Compounds disclosed herein can be crystallized and can be provided in asingle crystalline form or as a combination of different crystalpolymorphs. As such, the compounds can be provided in one or morephysical form, such as different crystal forms, crystalline, liquidcrystalline or non-crystalline (amorphous) forms. Such differentphysical forms of the compounds can be prepared using, for exampledifferent solvents or different mixtures of solvents forrecrystallization. Alternatively or additionally, different polymorphscan be prepared, for example, by performing recrystallizations atdifferent temperatures and/or by altering cooling rates duringrecrystallization. The presence of polymorphs can be determined by X-raycrystallography, or in some cases by another spectroscopic technique,such as solid phase NMR spectroscopy, IR spectroscopy, or bydifferential scanning calorimetry.

The pharmaceutical compositions can be administered to subjects by avariety of mucosal administration modes, including by oral, rectal,intranasal, intrapulmonary, or transdermal delivery, or by topicaldelivery to other surfaces. Optionally, the compositions can beadministered by non-mucosal routes, including by intramuscular,subcutaneous, intravenous, intra-arterial, intra-articular,intraperitoneal, intrathecal, intracerebroventricular, or parenteralroutes. In other alternative embodiments, the compound can beadministered ex vivo by direct exposure to cells, tissues or organsoriginating from a subject.

To formulate the pharmaceutical compositions, the compound can becombined with various pharmaceutically acceptable additives, as well asa base or vehicle for dispersion of the compound. Desired additivesinclude, but are not limited to, pH control agents, such as arginine,sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like.In addition, local anesthetics (for example, benzyl alcohol),isotonizing agents (for example, sodium chloride, mannitol, sorbitol),adsorption inhibitors (for example, Tween 80 or Miglyol 812), solubilityenhancing agents (for example, cyclodextrins and derivatives thereof),stabilizers (for example, serum albumin), and reducing agents (forexample, glutathione) can be included. Adjuvants, such as aluminumhydroxide (for example, Amphogel, Wyeth Laboratories, Madison, N.J.),Freund's adjuvant, MPLTM (3-O-deacylated monophosphoryl lipid A; Corixa,Hamilton, Ind.) and IL-12 (Genetics Institute, Cambridge, Mass.), amongmany other suitable adjuvants well known in the art, can be included inthe compositions. When the composition is a liquid, the tonicity of theformulation, as measured with reference to the tonicity of 0.9% (w/v)physiological saline solution taken as unity, is typically adjusted to avalue at which no substantial, irreversible tissue damage will beinduced at the site of administration. Generally, the tonicity of thesolution is adjusted to a value of about 0.3 to about 3.0, such as about0.5 to about 2.0, or about 0.8 to about 1.7.

The compound can be dispersed in a base or vehicle, which can include ahydrophilic compound having a capacity to disperse the compound, and anydesired additives. The base can be selected from a wide range ofsuitable compounds, including but not limited to, copolymers ofpolycarboxylic acids or salts thereof, carboxylic anhydrides (forexample, maleic anhydride) with other monomers (for example, methyl(meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers,such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone,cellulose derivatives, such as hydroxymethylcellulose,hydroxypropylcellulose and the like, and natural polymers, such aschitosan, collagen, sodium alginate, gelatin, hyaluronic acid, andnontoxic metal salts thereof. Often, a biodegradable polymer is selectedas a base or vehicle, for example, polylactic acid, poly(lacticacid-glycolic acid) copolymer, polyhydroxybutyric acid,poly(hydroxybutyric acid-glycolic acid) copolymer and mixtures thereof.Alternatively or additionally, synthetic fatty acid esters such aspolyglycerin fatty acid esters, sucrose fatty acid esters and the likecan be employed as vehicles. Hydrophilic polymers and other vehicles canbe used alone or in combination, and enhanced structural integrity canbe imparted to the vehicle by partial crystallization, ionic bonding,cross-linking and the like. The vehicle can be provided in a variety offorms, including fluid or viscous solutions. gels, pastes, powders,microspheres and films for direct application to a mucosal surface.

The compound can be combined with the base or vehicle according to avariety of methods, and release of the compound can be by diffusion,disintegration of the vehicle, or associated formation of waterchannels. In some circumstances, the compound is dispersed inmicrocapsules (microspheres) or nanocapsules (nanospheres) prepared froma suitable polymer, for example, isobutyl 2-cyanoacrylate (see, forexample, Michael et al., J. Pharmacy Pharmacol. 43:1-5, 1991), anddispersed in a biocompatible dispersing medium, which yields sustaineddelivery and biological activity over a protracted time.

The compositions of the disclosure can alternatively contain aspharmaceutically acceptable vehicles substances as required toapproximate physiological conditions, such as pH adjusting and bufferingagents, tonicity adjusting agents, wetting agents and the like, forexample, sodium acetate, sodium lactate, sodium chloride, potassiumchloride, calcium chloride, sorbitan monolaurate, and triethanolamineoleate. For solid compositions, conventional nontoxic pharmaceuticallyacceptable vehicles can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like.

Pharmaceutical compositions for administering the compound can also beformulated as a solution, microemulsion, or other ordered structuresuitable for high concentration of active ingredients. The vehicle canbe a solvent or dispersion medium containing, for example, water,ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like), and suitable mixtures thereof.Proper fluidity for solutions can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of a desired particlesize in the case of dispersible formulations, and by the use ofsurfactants. In many cases, it will be desirable to include isotonicagents, for example, sugars, polyalcohols, such as mannitol andsorbitol, or sodium chloride in the composition. Prolonged absorption ofthe compound can be brought about by including in the composition anagent which delays absorption, for example, monostearate salts andgelatin.

In certain embodiments, the compound can be administered in a timerelease formulation, for example in a composition which includes a slowrelease polymer. These compositions can be prepared with vehicles thatwill protect against rapid release, for example a controlled releasevehicle such as a polymer, microencapsulated delivery system orbioadhesive gel. Prolonged delivery in various compositions of thedisclosure can be brought about by including in the composition agentsthat delay absorption, for example, aluminum monostearate hydrogels andgelatin. When controlled release formulations are desired, controlledrelease binders suitable for use in accordance with the disclosureinclude any biocompatible controlled release material which is inert tothe active agent and which is capable of incorporating the compoundand/or other biologically active agent. Numerous such materials areknown in the art. Useful controlled-release binders are materials thatare metabolized slowly under physiological conditions following theirdelivery (for example, at a mucosal surface, or in the presence ofbodily fluids). Appropriate binders include, but are not limited to,biocompatible polymers and copolymers well known in the art for use insustained release formulations. Such biocompatible compounds arenon-toxic and inert to surrounding tissues, and do not triggersignificant adverse side effects, such as nasal irritation, immuneresponse, inflammation, or the like. They are metabolized into metabolicproducts that are also biocompatible and easily eliminated from thebody.

Exemplary polymeric materials for use in the present disclosure include,but are not limited to, polymeric matrices derived from copolymeric andhomopolymeric polyesters having hydrolyzable ester linkages. A number ofthese are known in the art to be biodegradable and to lead todegradation products having no or low toxicity. Exemplary polymersinclude polyglycolic acids and polylactic acids, poly(DL-lacticacid-co-glycolic acid), poly(D-lactic acid-co-glycolic acid), andpoly(L-lactic acid-co-glycolic acid). Other useful biodegradable orbioerodable polymers include, but are not limited to, such polymers aspoly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid),poly(epsilon.-aprolactone-CO-glycolic acid), poly(beta-hydroxy butyricacid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethylmethacrylate), polyamides, poly(amino acids) (for example, L-leucine,glutamic acid, L-aspartic acid and the like), poly(ester urea),poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers,polyorthoesters, polycarbonate, polymaleamides, polysaccharides, andcopolymers thereof. Many methods for preparing such formulations arewell known to those skilled in the art (see, for example, Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978). Other useful formulations includecontrolled-release microcapsules (U.S. Pat. Nos. 4,652,441 and4,917,893), lactic acid-glycolic acid copolymers useful in makingmicrocapsules and other formulations (U.S. Pat. Nos. 4,677,191 and4,728,721) and sustained-release compositions for water-soluble peptides(U.S. Pat. No. 4,675,189).

The pharmaceutical compositions of the disclosure typically are sterileand stable under conditions of manufacture, storage and use. Sterilesolutions can be prepared by incorporating the compound in the requiredamount in an appropriate solvent with one or a combination ofingredients enumerated herein, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thecompound and/or other biologically active agent into a sterile vehiclethat contains a basic dispersion medium and the required otheringredients from those enumerated herein. In the case of sterilepowders, methods of preparation include vacuum drying and freeze-dryingwhich yields a powder of the compound plus any additional desiredingredient from a previously sterile-filtered solution thereof. Theprevention of the action of microorganisms can be accomplished byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

In accordance with the various treatment methods of the disclosure, thecompound can be delivered to a subject in a manner consistent withconventional methodologies associated with management of the disorderfor which treatment or prevention is sought. In accordance with thedisclosure herein, a prophylactically or therapeutically effectiveamount of the compound and/or other biologically active agent isadministered to a subject in need of such treatment for a time and underconditions sufficient to prevent, inhibit, and/or ameliorate a selecteddisease or condition or one or more symptom(s) thereof.

The administration of the compound of the disclosure can be for eitherprophylactic or therapeutic purpose. When provided prophylactically, thecompound is provided in advance of any symptom. The prophylacticadministration of the compound serves to prevent or ameliorate anysubsequent disease process. When provided therapeutically, the compoundis provided at (or shortly after) the onset of a symptom of disease orinfection.

For prophylactic and therapeutic purposes, the compound can beadministered to the subject by the oral route or in a single bolusdelivery, via continuous delivery (for example, continuous transdermal,mucosal or intravenous delivery) over an extended time period, or in arepeated administration protocol (for example, by an hourly, daily orweekly, repeated administration protocol). The therapeutically effectivedosage of the compound can be provided as repeated doses within aprolonged prophylaxis or treatment regimen that will yield clinicallysignificant results to alleviate one or more symptoms or detectableconditions associated with a targeted disease or condition as set forthherein. Determination of effective dosages in this context is typicallybased on animal model studies followed up by human clinical trials andis guided by administration protocols that significantly reduce theoccurrence or severity of targeted disease symptoms or conditions in thesubject. Suitable models in this regard include, for example, murine,rat, avian, dog, sheep, porcine, feline, non-human primate, and otheraccepted animal model subjects known in the art. Alternatively,effective dosages can be determined using in vitro models. Using suchmodels, only ordinary calculations and adjustments are required todetermine an appropriate concentration and dose to administer atherapeutically effective amount of the compound (for example, amountsthat are effective to alleviate one or more symptoms of a targeteddisease). In alternative embodiments, an effective amount or effectivedose of the compound may simply inhibit or enhance one or more selectedbiological activities correlated with a disease or condition, as setforth herein, for either therapeutic or diagnostic purposes.

The actual dosage of the compound will vary according to factors such asthe disease indication and particular status of the subject (forexample, the subject's age, size, fitness, extent of symptoms,susceptibility factors, and the like), time and route of administration,other drugs or treatments being administered concurrently, as well asthe specific pharmacology of the compound for eliciting the desiredactivity or biological response in the subject. Dosage regimens can beadjusted to provide an optimum prophylactic or therapeutic response. Atherapeutically effective amount is also one in which any toxic ordetrimental side effects of the compound and/or other biologicallyactive agent is outweighed in clinical terms by therapeuticallybeneficial effects. A non-limiting range for a therapeutically effectiveamount of a compound and/or other biologically active agent within themethods and formulations of the disclosure is about 0.01 mg/kg bodyweight to about 20 mg/kg body weight, such as about 0.05 mg/kg to about5 mg/kg body weight, or about 0.2 mg/kg to about 2 mg/kg body weight.

Dosage can be varied by the attending clinician to maintain a desiredconcentration at a target site (for example, the lungs or systemiccirculation). Higher or lower concentrations can be selected based onthe mode of delivery, for example, trans-epidermal, rectal, oral,pulmonary, intraosseous, or intranasal delivery versus intravenous orsubcutaneous or intramuscular delivery. Dosage can also be adjustedbased on the release rate of the administered formulation, for example,of an intrapulmonary spray versus powder, sustained release oral versusinjected particulate or transdermal delivery formulations, and so forth.

The compounds disclosed herein may also be co-administered with anadditional therapeutic agent. Such agents include, but are not limitedto, an antidiabetic agent, a cholesterol-lowering agent, ananti-inflammatory agent, an antimicrobial agent, a matrixmetalloprotease inhibitor, a lipoxygenase inhibitor, a cytokineantagonist, an immunosuppressant, an anti-cancer agent, an anti-viralagent, a cytokine, a growth factor, an immunomodulator, a prostaglandinor an anti-vascular hyperproliferation compound.

The instant disclosure also includes kits, packages and multi-containerunits containing the herein described pharmaceutical compositions,active ingredients, and/or means for administering the same for use inthe prevention and treatment of diseases and other conditions inmammalian subjects. Kits for diagnostic use are also provided. In oneembodiment, these kits include a container or formulation that containsone or more of the compounds described herein. In one example, thiscomponent is formulated in a pharmaceutical preparation for delivery toa subject. The compound is optionally contained in a bulk dispensingcontainer or unit or multi-unit dosage form. Optional dispensing meanscan be provided, for example a pulmonary or intranasal spray applicator.Packaging materials optionally include a label or instruction indicatingfor what treatment purposes and/or in what manner the pharmaceuticalagent packaged therewith can be used.

EXAMPLES Illustrative Example 1

To the sulfonyl urea compound 3 (446 mg, 1.00 mmoles) in chlorobenzene 3mL (Synthesis Scheme 1) was added PCl₅ and the mixture was heated for 1h. The solvent was then evaporated and the imidoyl chloride residue wasdissolved in dichloromethane and treated with a pre-mixed mixture ofacetamidine hydrochloride (3.06 mmoles) in methanol:dichloromethane:Et₃N(2:1:1) at −78° C. dropwise and allowed to warm up to room temperatureovernight. The reaction mixture was extracted in to dichloromethanewashed with water and purified by flash chromatography using hexanes:EtOAC (6:4) to afford the amidino compound A above in 30-40% yield. Thecharacterization data is shown in Table 1.

Illustrative Example 2

To the acid Compound XIII (1.2 mg, 4 mmoles) in dichloromethaneSynthesis Scheme 2 was added EDCI (2eq), DMAP (2eq) and 2-napthalenesulfonamide (1.1 eq) ans stirred overnight. The mixture was thenacidified with IN HC1 and extracted with water and dichloromethane. Thedichloromethane layer was evaporated and the crude residue wastriturated with IPA to give the pure sulfonyl urea compound 4 in 40-50yield based on recovered material. The compound 4 was then taken up indichloromethane and PC15 and the mixture was heated at reflux for 24 h.The imidoyl chloride residue was dissolved in further dichloromethaneand treated with a pre-mixed mixture of methyl carbamimidothioatehydroiodide (2 mmoles) in methanol:dichloromethane:Et₃N (2:1:1) at −78°C. dropwise and allowed to wain up to room temperature overnight. Thereaction mixture was extracted in to dichloromethane washed with waterand purified by flash chromatography using hexanes: EtOAC (6:4) toafford the amidino compound B above in 50-60% yield. Thecharacterization data is shown in Table 4.

The compounds disclosed herein may have a high affinity for the mouseCB1 receptor in a radioligand displacement assay using mouse brainplasma membranes and ³H-CP55540 as the labeled ligand. For example,compound MRI-1950 has a K_(i)CB1 of 1.2 nM. In addition, the compoundsdisclosed herein may be less lipophilic. For example, compound MRI-1950has a CLogP value of 3.3 that makes it less lipophilic, consequentlyimproving its water solubility.

TABLE 1

K_(i) Serial CB1 Mass CLogP/tPSA # R¹ A (nM) H-NMR (400 MHz, CDCl3): MH⁼(theoretical)  1 Me CH₂  3 δ 7.54 (d, J = 7.5 Hz, 2H), 487.02 3.50/101.22 7.33-7.29 (m, 3H), 7.23-7.21 (m, 2H), 7.15 (d, J = 6.5 Hz,2H), 4.71-4.69 (m, 1H), 4.49- 4.43 (m, 1H), 4.04-4.00 (m, 1H), 3.12 (d,J = 0.7 Hz, 4H), 2.11 (s, 3H), 1.63 (t, J = 0.8 Hz, 5H), 1.46 (d, J =0.7 Hz, 2H).  2 CH₃CONH CH₂ 1.6 δ 7.65-7.63 (m, 2H), 7.31 530.04 3.96/130.32 (d, J = 7.0 Hz, 3H), 7.22-7.16 (m, 2H), 7.15 (d, J = 7.2Hz, 2H), 4.62 (s, 2H), 3.93 (s, 1H), 3.11 (m, 4H), 1.94 (s, 3H), 1.69(d, J = 2.8 Hz, 4H), 1.49 (s, 2H).  3 SMe CH₂ 15 δ 7.58 (s, 2H),7.35-7.31 (m, 519.08  4.39/101.22 2H), 7.29 (s, 1H), 7.21 (dd, J = 13.8,7.2 Hz, 4H), 4.70- 4.66 (m, 1H), 4.52-4.46 (m, 1H), 4.05-4.02 (m, 1H),3.13 (m, 4H), 2.52 (s, 3H), 1.65 (m, 4H), 1.47 (s, 2H).  4 t-Butyl CH₂23 δ 7.52 (s, 2H), 7.32 (d, J = 529.1  4.74/101.22 6.7 Hz, 3H),7.23-7.21 (m, 2H), 7.17 (s, 2H), 4.94 (s, 1H), 4.69-4.67 (m, 1H), 4.50-4.44 (m, 1H), 4.01-3.98 (m, 1H), 3.13 (m, 4H), 1.63 (t, J = 1.0 Hz, 4H),1.47 (s, 2H), 1.36 (s, 9H).  5 4-F-phenyl CH₂ δ 7.85 (s, 2H), 7.47-7.46(m, 567  6.43/101/22 2H), 7.21 (d, J = 5.0 Hz, 5H), 7.06 (t, J = 8.1 Hz,2H), 6.60-6.59 (m, 2H), 6.30-6.28 (bs, 2H), 4.52-4.49 (m, 1H), 4.33-4.30(m, 1H), 3.79 (s, 1H), 3.16 (s, 4H), 1.66 (s, 4H), 1.48 (s, 2H).  64-Cl-phenyl CH₂ δ 7.77 (d, J = 7.8 Hz, 2H), 583.5  7.00/101.22 7.46-7.44(m, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.9 Hz, 5H), 6.59-6.58(m, 2H), 6.25 (s, 2), 4.50 (dt, J = 9.3, 0.9 Hz, 1H), 4.31-4.29 (m, 1H),3.79-3.75 (m, 1H), 3.15 (m, 4H), 1.66 (m, 4H), 1.48 (s, 2H).  7 Me CF₂ δ7.54 (d, J = 7.6 Hz, 2H), 523.00  2.89/101.22 7.31 (t, J = 7.3 Hz, 3H),7.23 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 6.9 Hz, 2H), 5.39 (s, 1H),4.72-4.70 (m, 1H), 4.43 (t, J = 12.1 Hz, 1H), 4.01-3.97 (m, 1H), 3.33(m, 4H), 2.10 (d, J = 14.0 Hz, 7H).  8 CH₃CONH CF₂ 1.2 δ 7.63-7.61 (m,2H), 7.32 (d, 566.02  3.34/130.32 J = 6.9 Hz, 2H), 7.31-7.28 (m, 1H),7.22 (s, 2H), 7.16 (d, J = 7.0 Hz, 2H), 4.66-4.64 (m, 1H), 4.55-4.49 (m,1H), 3.97 (t, J = 5.8 Hz, 1H), 3.33 (m, 4H), 2.05 (m, 7H).  9 SMe CF₂ 14δ 7.58 (s, 2H), 7.33 (d, J = 555.06  3.77/101.22 7.1 Hz, 4H), 7.23-7.17(m, 3H), 4.70 (dddd, J = 5.5, 4.1, 2.6, 1.4 Hz, 1H), 4.50-4.45 (m, 1H),4.02 (ddd, J = 5.3, 2.6, 1.6 Hz, 1H), 3.35 (m, 4H), 2.52 (s, 3H), 2.10(s, mH). 10 t-Butyl CF₂ 21 δ 7.51 (s, 2H), 7.32 (q, J = 565.0841.2/101.22 7.6 Hz, 3H), 7.19 (dd, J = 26.8, 7.1 Hz, 4H), 4.94 (s, 1H),4.71-4.68 (m, 1H), 4.44 (t, J = 11.4 Hz, 1H), 3.99- 3.95 (m, 1H), 3.35(m, 4H), 2.08 (s, mH), 1.37 (s, 9H). 11 4-F-phenyl CF₂ δ 7.85 (dd, J =7.0, 5.2 Hz, 603.06  5.82/101.22 2H), 7.46 (td, J = 1.8, 1.1 Hz, 2H),7.23 (m, 5H), 7.09 (t, J = 8.2 Hz, 2H), 6.60 (dt, J = 2.0, 1.3 Hz, 2H),6.03-5.99 (m, 2H), 4.52 (td, J = 3.7, 2.6 Hz, 1H), 4.31-4.27 (m, 1H),3.79-3.76 (m, 1H), 3.37 (m, 4H), 2.10 (m, 4H). 12 4-Cl-phenyl CF₂ δ 7.77(d, J = 8.1 Hz, 2H), 619.5  6.57/101.22 7.46-7.44 (m, 2H), 7.38 (d, J =8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 5H), 6.57 (s, 2H), 6.11 (s, 2H),4.53-4.50 (m, 1H), 4.28 (t, J = 6.6 Hz, 1H), 3.76-3.74 (m, 1H), 3.37 (d,J = 0.9 Hz, 4H), 2.10 (m, 4H). 13 Me CH  3 δ 7.54 (d, J = 7.6 Hz, 2H),555.02  3.59/101.22 CF₃ 7.33-7.29 (m, 3H), 7.23 (d, J = 7.8 Hz, 2H),7.14 (d, J = 7.1 Hz, 2H), 5.34 (s, 1H), 4.70-4.69 (m, 1H), 4.47-4.41 (m,1H), 4.01-3.97 (m, 1H), 3.86 (m, 2H), 2.63-2.60 (m, 2H), 2.11 (s, 3H),2.04 (s, 1H), 1.86 (m, 2H), 1.74-1.71 (m, 2H). 14 CH₃CONH CH δ 7.62 (dt,J = 4.3, 2.1 Hz, 598.04  4.05/130.32 CF₃ 2H), 7.33-7.29 (m, 3H), 7.26-7.21 (m, 3H), 7.17-7.15 (m, 1H), 4.68-4.64 (m, 1H), 4.56- 4.49 (m, 1H),3.99-3.95 (m, 1H), 3.88-3.84 (m, 2H), 2.58- 2.52 (m, 2H), 2.10 (d, J =0.6 Hz, 4H), 1.92-1.84 (m, 2H), 1.77-1.70 (m, 2H). 15 SMe CH δ 7.57 (s,2H), 7.31 (t, J = 587.08  4.48/101.22 CF₃ 8.0 Hz, 3H), 7.23 (d, J = 8.1Hz, 2H), 7.18 (d, J = 6.1 Hz, 2H), 5.33 (s, 1H), 4.72-4.68 (m, 1H),4.49-4.46 (m, 1H), 4.02-3.99 (m, 1H), 3.86-3.84 (m, 2H), 2.65-2.53 (m,5H), 2.08-2.04 (m, 1H), 1.91-1.88 (m, 2H), 1.75-1.72 (m, 2H). 16 t-ButylCH δ 7.52 (s, 2H), 7.33-7.29 (m, 597.10  4.83/101.22 CF₃ 3H), 7.23 (d, J= 8.5 Hz, 2H), 7.15 (t, J = 0.7 Hz, 2H), 4.93 (s, 2H), 4.71-4.67 (m,1H), 4.47-4.41 (m, 1H), 4.00-3.96 (m, 1H), 3.88-3.85 (m, 2H), 2.64-2.59(m, 2H), 2.04 (s, 1H), 1.90-1.86 (m, 2H), 1.75- 1.71 (m, 2H), 1.37 (s,9H). 17 Me O δ 7.54 (d, J = 7.7 Hz, 2H), 488.99  3.21/110.45 7.35-7.29(m, 3H), 7.15 (d, J = 6.7 Hz, 4H), 5.28 (s, 1H), 4.77-4.69 (m, 1H),4.49-4.38 (m, 1H), 4.03-3.99 (m, 1H), 3.75 (m, 4H), 3.16-3.11 (m, 4H),2.11 (s, 3H). 18 SMe O δ 7.59 (s, 2H), 7.32 (d, J = 521.06  3.83/110.456.9 Hz, 3H), 7.24-7.18 (m, 4H), 4.71-4.69 (m, 1H), 4.52- 4.47 (m, 1H),4.06-4.00 (m, 1H), 3.77 (m, 4H), 3.17 (m, 4H), 2.52 (s, 3H). 19*4-F-phenyl CH δ 7.82 (dd, J = 8.7, 5.3 Hz, 636.08  6.5/101.2 CF₃ 2H),7.46-7.44 (m, 2H), 7.25- 7.19 (m, 5H), 7.04 (t, J = 8.6 Hz, 2H), 6.57(s, 2H), 6.43 (s, 2H), 4.51-4.48 (m, 1H), 4.30-4.25 (m, 1H), 3.87 (t, J= 10.3 Hz, 2H), 3.79-3.75 (m, 1H), 2.69-2.59 (m, 2H), 2.07 (d, J = 16.0Hz, 1H), 1.90 (d, J = 13.0 Hz, 2H), 1.78-1.70 (m, 2H). 20 4-Cl-phenyl CHδ 7.77 (d, J = 8.4 Hz, 2H), 651.53  7.2/101.22 CF₃ 7.46-7.45 (m, 2H),7.37 (d, J = 8.4 Hz, 2H), 7.22 (t, J = 6.1 Hz, 5H), 6.63 (s, 2H), 5.97(s, 2H), 4.55-4.51 (m, 1H), 4.33-4.27 (m, 1H), 3.92- 3.86 (m, 2H),3.79-3.75 (m, 1H), 2.69-2.59 (m, 2H), 2.08- 2.05 (m, 1H), 1.89 (d, J =8.1 Hz, 2H), 1.79-1.71 (m, 2H). 21 4-F-phenyl O δ 7.85 (dd, J = 8.3, 5.4Hz, 569.05  5.62/110.4 2H), 7.50 (d, J = 25.1 Hz, 2H), 7.22-7.20 (m,5H), 7.07 (t, J = 8.4 Hz, 2H), 6.63 (s, 2H), 6.09-6.06 (m, 2H), 4.54-4.51 (m, 1H), 4.36-4.30 (m, 1H), 3.84-3.82 (m, 5H), 3.19 (s, 4H). 224-Cl-phenyl O δ 7.75 (t, J = 8.8 Hz, 2H), 7.45-7.37 (m, 2H), 7.37-7.32(m, 2H), 7.23 (t, J = 9.7 Hz, 5H), 6.58 (s, 2H), 6.20 (s, 2H), 4.52-4.50(m, 1H), 4.32- 4.28 (m, 1H), 3.76 (s, 5H), 3.18 (s, 4H). 585.5 6.19/110.4 23 CH₃CONH O δ 7.63 (d, J = 8.3 Hz, 2H), 532.02  3.53/139.57.31 (q, J = 7.9 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz,3H), 4.66 (dd, J = 11.5, 5.8 Hz, 1H), 4.52 (t, J = 11.8 Hz, 1H), 4.00(dd, J = 12.0, 5.9 Hz, 1H), 3.76 (d, J = 3.4 Hz, 4H), 3.18 (d, J = 3.2Hz, 4H), 2.09 (s, 3H). 24 t-Butyl O δ 7.53 (s, 2H), 7.32 (t, J = 531.07 4.4/110.4 7.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 8.6 Hz,2H), 7.16 (d, J= 7.2 Hz, 2H), 4.68 (dd, J = 11.5, 5.5 Hz, 1H), 4.46 (t,J = 11.9 Hz, 1H), 4.00 (dd, J = 12.1, 5.5 Hz, 1H), 3.75 (s, 4H), 3.17(s, 4H), 1.35 (s, 9H). 25 SMe CH δ 7.59-7.58 (m, 2H), 7.30 595.1 5.8/101.2 Ph (dd, J = 17.9, 7.4 Hz, 3H), 7.21 (dd, J = 14.7, 8.1 Hz,4H), 4.70 (dd, J = 11.5, 5.4 Hz, 1H), 4.51 (t, J = 11.8 Hz, 1H), 4.05(dd, J = 12.1, 5.2 Hz, 1H), 3.92-3.87 (m, 2H), 2.76-2.67 (m, 2H), 2.53(s, 3H), 1.88 (d, J = 3.4 Hz, 3H). 26 Me CH Ph 563.11  4.9/101.22

TABLE 2

K_(i) Serial CB₁ CLogP/tPSA # R¹ R² R³ (nM) H-NMR Mass (theoretical) 1Me Et Et δ 7.53 (d, J = 8.5 Hz, 2H), 475.16 2.67/101.22 7.30 (q, J = 7.5Hz, 3H), 7.21 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 7.0 Hz, 2H), 5.34 (s,1H), 4.67 (dd, J = 11.6, 5.3 Hz, 1H), 4.42 (t, J = 12.0 Hz, 1H), 3.99(dd, J = 12.3, 5.3 Hz, 1H), 3.25 (q, J = 7.3 Hz, 4H), 2.10 (s, 3H), 1.18(dt, J = 13.9, 6.8 Hz, 7H) 2 SMe Et Et δ 7.57 (s, 2H), 7.32-7.31 (m,508.08 3.74/101.22 3H), 7.22 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 5.8 Hz,2H), 4.69-4.65 (m, 1H), 4.49-4.43 (m, 1H), 4.04-3.99 (m, 1H), 3.26 (d, J= 6.7 Hz, 4H), 2.52 (s, 3H), 1.19 (m, 6H). 3 t-Butyl Et Et δ 7.51 (d, J= 8.3 Hz, 2H), 517.09 3.91/101.22 7.29 (t, J = 8.3 Hz, 3H), 7.21 (d, J =8.6 Hz, 2H), 7.15 (d, J = 7.2 Hz, 2H), 4.65 (dd, J = 11.6, 5.6 Hz, 1H),4.42 (t, J = 11.9 Hz, 1H), 3.97 (dd, J = 12.2, 5.6 Hz, 1H), 3.25 (q, J =7.1 Hz, 4H), 1.36 (s, 9H), 1.17 (t, J = 7.1 Hz, 6H). 4 CH₃CONH Et Et δ8.50 (s, 1H), 7.61 (d, J = 518.03 3.31/130.3 8.3 Hz, 2H), 7.30-7.25 (m,3H), 7.21 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 7.1 Hz, 2H), 4.63 (dd, J =11.0, 5.4 Hz, 1H), 4.52- 4.46 (m, 1H), 4.01-3.97 (m, 1H), 3.24 (q, J =7.1 Hz, 4H), 2.09 (s, 3H), 1.19 (t, J = 7.2 Hz, 6H). 5 4-F-phenyl Et Etδ 7.89 (dd, J = 8.6, 5.3 Hz, 555.07 5.7/101.22 2H), 7.49-7.47 (m, 2H),7.22- 7.19 (m, 5H), 7.10 (t, J = 8.6 Hz, 2H), 6.78 (s, 2H), 5.6 (bs,1H), 4.56-4.52 (m, 1H), 4.37- 4.30 (m, 1H), 3.89-3.86 (m, 1H), 3.28 (q,J = 7.1 Hz, 4H), 1.19 (t, J = 7.1 Hz, 6H). 6 4-Cl-phenyl Et Et δ 7.79(d, J = 8.3 Hz, 2H), 571.5 6.35/101.22 7.47-7.45 (m, 2H), 7.35 (d, J =8.3 Hz, 2H), 7.21 (t, J = 7.0 Hz, 5H), 6.68 (s, 2H), 6.00 (s, 2H),4.53-4.49 (m, 1H), 4.33- 4.27 (m, 1H), 3.82-3.77 (m, 1H), 3.28 (q, J =7.1 Hz, 4H), 1.19 (dd, J = 8.8, 6.0 Hz, 6H). 7 t-Butyl i-Pr i-pr 545.14.5/101.22

TABLE 3

K_(i) Serial CB₁ CLogP/tPSA # R¹ A (nM) H-NMR Mass (theoretical) 1 MeCH₂ δ 7.52 (s, 2H), 7.33-7.26 (m, 3H), 473 2.94/101.22 7.22 (d, J = 8.6Hz, 2H), 7.15 (s, 2H), 5.21 (s, 2H), 4.68 (ddd, J = 11.5, 5.3, 0.3 Hz,1H), 4.46-4.40 (m, 1H), 4.01-3.97 (m, 1H), 3.33- 3.30 (m, 4H), 2.11 (s,3H), 1.85- 1.82 (m, 4H). 2 SMe CH₂ δ 7.57 (s, 2H), 7.32 (dd, J = 6.7,505.06 3.83/101.22 0.8 Hz, 3H), 7.23 (d, J = 8.2 Hz, 2H), 7.23 (d, J =8.2 Hz, 2H), 4.68 (d, J = 9.6 Hz, 1H), 4.49-4.43 (m, 1H), 4.01 (d, J =16.1 Hz, 1H), 3.34 (m, 4H), 2.53 (s, 3H), 1.86 (m, 4H). 3 4-F-phenyl CH₂¹H-NMR (400 MHz, CDCl₃): δ 553.05 5.87/101.22 7.88 (dd, J = 8.3, 5.4 Hz,2H), 7.47 (d, J = 7.4 Hz, 2H), 7.21 (d, J = 8.5 Hz, 5H), 7.08 (t, J =8.4 Hz, 2H), 6.70 (s, 2H), 5.94 (s, 2H), 4.54-4.50 (m, 1H), 4.35-4.28(m, 1H), 3.84- 3.80 (m, 1H), 3.35 (d, J = 5.7 Hz, 4H), 1.86 (s, 4H). 44-Cl-phenyl CH₂ H-NMR (400 MHz, CDCl₃): δ 7.79 569.51 6.4/101.2 (d, J =8.4 Hz, 2H), 7.50-7.41 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.21 (t, J =6.5 Hz, 5H), 6.64 (s, 2H), 6.13 (s, 2H), 4.52-4.49 (m, 1H), 4.34-4.26(m, 1H), 3.81-3.75 (m, 1H), 3.35 (d, J = 6.8 Hz, 4H), 1.86 (s, 4H). 5CH₃CONH CH₂ 516.02 3.4/130.3 6 t-Butyl CH₂ δ 7.52-7.50 (m, 2H), 7.31 (q,J = 515.07 4.18/101.2 7.8 Hz, 4H), 7.21 (d, J = 8.5 Hz, 2H), 7.15 (d, J= 7.3 Hz, 2H), 4.66 (dd, J = 11.7, 5.6 Hz, 1H), 4.43 (t, J = 12.0 Hz,1H), 3.98 (dd, J = 12.2, 5.6 Hz, 1H), 3.32 (t, J = 6.3 Hz, 4H), 1.84 (t,J = 6.3 Hz, 4H), 1.36 (s, 9H).

TABLE 4

K_(i) Serial CB₁ CLogP/tPSA # R¹ R¹² (nM) H-NMR Mass (theoretical) 14-Cl-phenyl Fused Ph— 626.5 9.8/97.9 2 SMe Fused Ph 8.51 (s, 1H), 7.94-562 7.7/97.9 7.87 (m, 3H), 7.58 (t, J = 8.4 Hz, 2H), 7.28 (t, J = 5.2Hz, 6H), 7.12-7.07 (m, 3H), 6.92 (d, J = 8.9 Hz, 2H), 5.70 (s, 2H), 5.37(dd, J = 13.1, 6.6 Hz, 1H), 3.75 (dd, J = 17.9, 13.1 Hz, 1H), 3.12-3.06(m, 1H), 2.21 (s, 3H). 3 4-F-phenyl Fused Ph— 610.1 9.3/97.9 4 Me FusedPh 528.02 6.17/97.9 5 t-Butyl Fused Ph 570.1 7.4/97.9 6 CH₃CONH Fused Ph571.05 5.74/127.08 7 SMe CF₃ 580.04 7.43/97.9 8 t-Butyl CF₃ 590.067.7/97.9 9 SMe Cl 546.5 7.2/97.9Several embodiments are described below in the following numberedclauses:

1. A compound, or a pharmaceutically acceptable salt or ester thereof,having a structure of:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy;

R¹, R², and R³ are each independently selected from H,optionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, optionally-substituted phosphinyl,aralkyl, optionally-substituted thiol, or R² and R³ together with Z forman optionally-substituted cycloalkyl ring or an optionally-substitutedheterocycloalkyl ring;

Z is B, N, —CH—, or P;

D is —S(O)₂— or —C(O)—; and

n is 0 to 5.

2. The compound of clause 1, wherein R² and R³ together with Z do notform an optionally-substituted cycloalkyl ring or anoptionally-substituted heterocycloalkyl ring.

3. The compound of clause 2, wherein R² and R³ are each independentlyoptionally-substituted alkyl.

4. The compound of clause 3, wherein R² and R³ are each the same and areeach lower alkyl, and Z is N.

5. The compound of clause 1, wherein the compound has a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.

6. The compound of any one of clauses to 1 to 5, wherein each of X and Yis an optionally-substituted aryl.

7. The compound of clause 5, wherein the compound has a structure of:

wherein each of R⁴, R¹⁰ and R¹¹ is independently selected fromoptionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, monoor di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono ordi-substituted C-aryl, mono or di-substituted C-cycloalkyl,—CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ isH or alkyl;

a and b are each 0 to 5; and

c is 0 to 7.

8. The compound of clause 7, wherein the compound has a structure of:

9. The compound of clause 8, wherein the compound has a structure of:

10. The compound of clause 7, wherein the compound has a structure of:

11. The compound of clause 10, wherein the compound has a structure of:

12. A compound, or a pharmaceutically acceptable salt or ester thereof,having a structure of:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy; and

U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl,optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy,optionally-substituted alkoxy, amino, optionally-substituted sulfonyl,optionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted carboxyl, acyl, optionally-substituted alkenyl,optionally-substituted alkynyl, optionally-substituted phosphonyl, oroptionally-substituted phosphinyl; and R^(b) is a substituted sulfonylor a substituted carbonyl.

13. The compound of clause 12. wherein the compound has a structure of:

wherein R², and R³ are each independently selected from H,optionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, optionally-substituted phosphinyl, orR² and R³ together with Z form an optionally-substituted cycloalkylring, an optionally-substituted heterocycloalkyl ring; anoptionally-substituted aryl ring, or an optionally-substitutedheteroaryl ring;

Z is B, N, —CH—, or P; and

n is 0 to 5.

14. The compound of clause 13, wherein R² and R³ together with Z do notform an optionally-substituted cycloalkyl ring, anoptionally-substituted heterocycloalkyl ring; an optionally-substitutedaryl ring, or an optionally-substituted heteroaryl ring.

15. The compound of clause 13, R² and R³ are each independentlyoptionally-substituted alkyl (particularly lower alkyl).

16. The compound of clause 15, wherein R² and R³ are each the same andare each lower alkyl, and Z is N.

17. The compound of clause 13, wherein the compound has a structure of:

wherein each R¹² is independently selected from optionally-substitutedalkyl, optionally-substituted heteroalkyl, hydroxy,optionally-substituted alkoxy or optionally-substituted alkylamino,optionally-substituted aryl, halogen, cyano, nitro, acyl or carbonyl;and d is 0 to 5.

18. The compound of clause 13, wherein the compound has a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.

19. The compound of clause 18, wherein the compound has a structure of:

wherein each of R¹³, R¹⁴ and R¹⁵ is independently selected fromoptionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, monoor di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono ordi-substituted C-aryl, mono or di-substituted C-cycloalkyl,—CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ isH or alkyl;

f and g are each 0 to 5; and

g is 0 to 7.

20. The compound of clause 19, wherein the compound has a structure of:

21. The compound of clause 20, wherein the compound has a structure of:

22. The compound of clause 19, wherein the compound has a structure of:

23. The compound of clause 22, wherein the compound has a structure of:

24. The compound of any one of clauses 1 to 23, wherein R¹ isoptionally-substituted alkyl (e.g., lower alkyl, thiol-substituted loweralkyl), aminocarbonyl acetamido), or optionally-substituted phenyl(e.g., halogen-substituted phenyl).

25. The compound of any one of clauses 1 to 24, wherein Q is H.

26. The compound of any one of clauses 1 to 25, wherein A is —CH₂—,—CF₂—, —O—, or —CH(CF₃)—.

27. A pharmaceutical composition comprising a compound of any one ofclauses 1 to 26, and at least one pharmaceutically acceptable additive.

28. A pharmaceutical composition comprising a unit dosage form of atherapeutic amount of a compound of any one of clauses 1 to 26, and atleast one pharmaceutically acceptable additive.

29. A method for treating obesity, diabetes, non-alcoholic and alcoholicfatty liver disease, a co-morbidity of obesity, dyslipidemias thatpredispose to arteriosclerotic heart disease, diabetic nephropathy, orgout, in a subject, comprising administering to the subject in needthereof a therapeutically effective amount of a compound of any one ofclauses 1 to 26.

30. The method of claim 29, comprising treating obesity in the subject.

31. The method of claim 29, comprising treating diabetes in the subject.

32. A method of preventing or reversing the deposition of adipose tissuein a subject, comprising administering to the subject in need thereof aneffective amount of a compound of any one of clauses 1 to 26.

33. The method of any one of clauses 29 to 32, wherein administering ofthe compound causes substantially no adverse neuropsychiatric effects.

34. The method of any one of clauses 29 to 34, wherein administering ofthe compound results in a ratio of maximum concentration in the brain tomaximum concentration in plasma which is less than 0.1

In view of the many possible embodiments to which the principles of thedisclosed compounds, compositions and methods may be applied, it shouldbe recognized that the illustrated embodiments are only preferredexamples of the invention and should not be taken as limiting the scopeof the invention.

The invention claimed is:
 1. A compound, or a pharmaceuticallyacceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected fromoptionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted cycloalkyl, optionally-substitutedheterocycloalkyl, or optionally-substituted alkyl; Q is H, hydroxyl, oroptionally-substituted alkoxy; R¹, R², and R³ are each independentlyselected from H, optionally-substituted alkyl, optionally-substitutedcycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substitutedalkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl,optionally-substituted aryl, optionally-substituted heteroaryl,optionally-substituted carboxyl, acyl, optionally-substituted alkenyl,optionally-substituted alkynyl, optionally-substituted phosphonyl,optionally-substituted phosphinyl, aralkyl, optionally-substitutedthiol, or R² and R³ together with Z form an optionally-substitutedcycloalkyl ring or an optionally-substituted heterocycloalkyl ring; Z isB, N, —CH—, or P; D is —S(O)₂— or —C(O)—; and n is 0 to
 5. 2. Thecompound of claim 1, wherein R² and R³ together with Z do not form anoptionally-substituted cycloalkyl ring or an optionally-substitutedheterocycloalkyl ring.
 3. The compound of claim 2, wherein R² and R³ areeach independently optionally-substituted alkyl.
 4. The compound ofclaim 3, wherein R² and R³ are each the same and are each lower alkyl,and Z is N.
 5. The compound of claim 1, wherein the compound has astructure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.
 6. The compoundof claim 1, wherein each of X and Y is an optionally-substituted aryl.7. The compound of claim 5, wherein the compound has a structure of:

wherein each of R⁴, R¹⁰ and R¹¹ is independently selected fromoptionally-substituted alkyl, optionally-substituted cycloalkyl,halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino,optionally-substituted sulfonyl, optionally-substituted aryl,optionally-substituted heteroaryl, optionally-substituted carboxyl,acyl, optionally-substituted alkenyl, optionally-substituted alkynyl,optionally-substituted phosphonyl, or optionally-substituted phosphinyl;A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, monoor di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono ordi-substituted C-aryl, mono or di-substituted C-cycloalkyl,—CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ isH or alkyl; a and b are each 0 to 5; and c is 0 to
 7. 8. The compound ofclaim 7, wherein the compound has a structure of:


9. The compound of claim 8, wherein the compound has a structure of:


10. The compound of claim 7, wherein the compound has a structure of:


11. The compound of claim 10, wherein the compound has a structure of:


12. The compound of claim 1, wherein R¹ is optionally-substituted alkyl,aminocarbonyl optionally-substituted phenyl, or optionally-substitutedthiol.
 13. The compound of claim 1, wherein Q is H.
 14. The compound ofclaim 1, wherein D is —S(O)₂—.
 15. The compound of claim 1, wherein n is0.
 16. The compound of claim 1, wherein X and Y are eachoptionally-substituted phenyl, and Q is H.
 17. The compound of claim 1,wherein R¹ is —SMe.
 18. The compound of claim 7, wherein A is —CH₂—,—CF₂—, —O—, or —CH(CF₃)—.
 19. The compound of claim 8, wherein R¹ is—SMe.
 20. The compound of claim 8, wherein A is —CH(CF₃)—.
 21. Thecompound of claim 8, wherein Q is H, and c is
 0. 22. The compound ofclaim 9, wherein R¹ is —SMe.
 23. The compound of claim 22, wherein A is—CH(CF₃)—.
 24. The compound of claim 23, wherein Q is H, and c is
 0. 25.The compound of claim 9, wherein A is —CH(CF₃)—.
 26. The compound ofclaim 9, wherein Q is H, and c is
 0. 27. A pharmaceutical compositioncomprising a compound of claim 1, and at least one pharmaceuticallyacceptable additive.
 28. A pharmaceutical composition comprising a unitdosage form of a therapeutic amount of a compound of claim 1, and atleast one pharmaceutically acceptable additive.
 29. A pharmaceuticalcomposition comprising a unit dosage form of a therapeutic amount of acompound of claim 24, and at least one pharmaceutically acceptableadditive.
 30. A method for treating obesity, diabetes, non-alcoholic andalcoholic fatty liver disease, dyslipidemias that predispose toarteriosclerotic heart disease, diabetic nephropathy, or gout, in asubject, comprising administering to the subject in need thereof atherapeutically effective amount of a compound of claim
 1. 31. Themethod of claim 30, comprising treating obesity in the subject.
 32. Themethod of claim 30, comprising treating diabetes in the subject.
 33. Themethod of claim 30, wherein administering of the compound causessubstantially no adverse neuropsychiatric effects.
 34. The method ofclaim 30, wherein administering of the compound results in a ratio ofmaximum concentration in the brain to maximum concentration in plasmawhich is less than 0.1.
 35. A method of preventing or reversing thedeposition of adipose tissue in a subject, comprising administering tothe subject in need thereof an effective amount of a compound of claim1.